Treatment of Alzheimer&#39;s Disease Using Compounds that Reduce the Activity of Non-Selective CA++ Activated ATP-Sensitive Cation Channels Regulatd by SUR1 Channels

ABSTRACT

NSC antagonists are disclosed as useful in the treatment of dementia, in delaying the onset of dementia, and in the prevention of dementia. Dementia so treated may be, for example, Alzheimer&#39;s Disease (AD). NSC antagonists for treating dementia such as AD may be administered alone, a) in combination with other drugs used for treating dementia, b) in combination with drugs that stabilize or increase blood plasma glucose levels, or with both a) and b). Pharmaceutical compositions, dosage forms, and methods for using the same are disclosed, which include NSC antagonists, NSC antagonists combined with dementia drugs, NSC antagonists combined with glucose-level stabilizing or enhancing drugs, or combinations of these. Dosage forms may be designed to provide stable plasma levels for extended periods of time. Exemplary pharmaceutical compositions include compositions including glibenclamide and memantine; glibenclamide and donepezil; tolbutamide and memantine; tolbutamide and donepezil; and these compositions further including glucagon and/or glucose.

BACKGROUND

This application is a national phase application claiming priority under35 U.S.C. §120 from PCT/US07/081128 filed on Oct. 11, 2007, and claimsthe benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application60/851,412 filed Oct. 12, 2006, the entire disclosures of whichapplications are hereby incorporated by reference in their entireties.

Sulfonylurea drugs and related drugs are believed to act on the type 1sulfonylurea receptor (SUR1 receptor) and the type 2 sulfonylureareceptor (SUR2). Sulfonylurea drugs have been shown to be effective intreating stroke and spinal cord injury due to the drug acting on a nonselective cation channel which has type 1 sulfonylurea receptor (SUR1)binding sites and thus binds to Sulfonylureas. This channel is anon-selective Ca⁺⁺-activated ATP-sensitive cation channel termed the“NC_(Ca-ATP) channel” (see, e.g., Chen and Simard, Journal ofNeuroscience 21:6512-6521 (2001); and Chen et al., Journal ofNeuroscience 23:8568-8577 (2003), each hereby incorporated by reference)and is believed to include a regulatory sub-unit including a SUR1receptor, and a pore subunit that has similar properties to, and may becomprised of, a TRPM4 channel (see, e.g., Simard et al., Biochimica etBiophysica Acta, 1772(8):947-957 (2007), hereby incorporated byreference). There is also some ex-vivo evidence that certainSulfonylureas may have an effect in treating Parkinson's disease, andthe K_(ATP) channel has been implicated in this regard.

There have been numerous studies as to the association betweenAlzheimer's disease (AD) and Type 2 Diabetes. Type 2 Diabetes has beenfound to be both negatively and positively associated with AD. Thus,according to the scientific literature, the relationship, if any,between Type 2 Diabetes and AD remains unknown.

Dementia is a term describing loss of mental function in a patient. Asused herein, the term “dementia” refers to broadly to a psychiatric ormedical condition characterized by cognitive deficits that may includeimpairments in memory, reasoning, planning, and judgment. Seniledementia is a dementia having an onset at an advanced age. One form ofdementia that is more frequent in aged than in younger individuals ismulti-infarct dementia, characterized by brain damage resulting frommultiple infarcts, or strokes. Other forms of brain injury, braintrauma, inflammation, or other insult to the brain may lead to orexacerbate dementia. Another form of dementia, Alzheimer's Disease (AD),is a particularly prevalent form of dementia, and is more frequentlyfound in aged than in younger individuals.

AD is the most common form of dementia among older people, and initiallyinvolves the parts of the brain that control thought, memory, andlanguage. There are classic histolopathologic findings in AD such asneurofibrillary tangles, neuritic (senile) plaques, Hirano bodies,granulovacuolar bodies of Simchowicz, Pick bodies and Lewy bodies. Manyof these histopathologic findings are associated with neuronal celldeath which occurs insidiously many years before symptoms manifest.

SUMMARY

Applicants disclose herein the use of sulfonylurea receptor antagonistsand of blockers of non-selective channels (the NC_(Ca-ATP) channel, theTRPM4 channel, and the TRPM5 channel) to treat dementia. The use ofSulfonylureas, active metabolites of Sulfonylureas, Sulfonylureamimetics, or any drug or chemical compound effective to antagonize asulfonylurea receptor 1 (SUR1 receptor) or to block or reduce thephysiological activity of channels associated with SUR1 receptors, forameliorating dementia, for ameliorating the effects of dementia, fortreating dementia, for reducing the effects of dementia, or forpreventing or delaying the onset of dementia is disclosed herein.Sulfonylureas, Sulfonylurea mimetics, or any drug or chemical compoundselective for SUR1 receptors that antagonize SUR1 receptors, or areeffective to block or reduce the physiological activity of channelsassociated with SUR1 receptors, including antagonists and blockers ofthe NC_(Ca-ATP) channel and antagonists and blockers of the TRPM4channel and the TRPM5 channel, are collectively termed herein “NSCantagonists” referring to the common action of antagonizing the activityof the non-selective channels the NC_(Ca-ATP) channel (regulated by SUR1receptors) and the TRPM4 channel and the TRPM5 channel. A particularform of dementia treated by the methods, compositions, and formulationsdisclosed herein is Alzheimer's Disease (AD).

Thus, the use of NSC antagonists for treating AD, reducing the effectsof AD, or delaying or preventing the onset of AD is disclosed herein.Thus, methods, pharmaceutical compositions and formulations for thetreatment, palliation, amelioration, slowing the progression of, orprevention of AD are disclosed herein.

Embodiments of the invention disclosed herein include the use of a NSCantagonist in the manufacture of a medicament for the treatment ofdementia, including wherein the dementia is Alzheimer's Disease (AD).For example, a NSC antagonist for use in the manufacture of a medicamentfor the treatment of dementia, may be selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens,phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumicacid, rimonabant, SKF 9635, and combinations thereof.

In embodiments of the invention disclosed herein, a NSC antagonist isused together with an other compound in the manufacture of a medicamentfor the treatment of dementia, such as, e.g., AD, wherein the othercompound is a compound used in the treatment of dementia. For example,an other compound used in the treatment of dementia may be selected frommemantine, donepezil, galantamine, rivastigmine, tacrine, andcombinations thereof.

In further embodiments of the invention disclosed herein, the NSCantagonist used in the manufacture of a medicament for the treatment ofdementia, such as, e.g., AD, may comprises a combination of compoundscomprising a) at least one compound selected from: glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, andphytoestrogens; and b) at least one compound selected from: pinkolant,flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635.

In yet further embodiments, the NSC antagonist used in the manufactureof medicaments having features of the invention is selected from:glibenclamide, 4-trans-hydroxy-glibenclamide,3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide,repaglinide, nateglinide, meglitinide, midaglizole, tolazamide,gliquidone, LY397364, LY389382, glyclazide, and glimepiride. In stillfurther embodiments, the NSC antagonist used in the manufacture ofmedicaments having features of the invention is glibenclamide. In yetfurther embodiments, the NSC antagonist used in the manufacture ofmedicaments having features of the invention is selected from pinkolant,flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF9635. In a further embodiment, the NSC antagonist used in themanufacture of medicaments having features of the invention ispinkolant.

Further embodiments of the invention disclosed herein include apharmaceutical composition comprising a NSC antagonist; an othercompound used in the treatment of dementia; and a pharmaceuticallyacceptable carrier. For example, a NSC antagonist suitable for such apharmaceutical composition may be selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens,phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumicacid, rimonabant, SKF 9635, and combinations thereof. For example, another compound used in the treatment of dementia suitable for inclusionin a such pharmaceutical composition may be selected from memantine,donepezil, galantamine, rivastigmine, tacrine, and combinations thereof.

Further embodiments of pharmaceutical compositions having features ofthe invention include pharmaceutical compositions comprisingglibenclamide; a compound selected from memantine, donepezil,galantamine, rivastigmine, tacrine, and combinations thereof; and apharmaceutically acceptable carrier. In further embodiments, apharmaceutical composition comprises tolbutamide; a compound selectedfrom memantine, donepezil, galantamine, rivastigmine, tacrine, andcombinations thereof; and a pharmaceutically acceptable carrier. In yetfurther embodiments, a pharmaceutical composition compriseschlorpropamide; a compound selected from memantine, donepezil,galantamine, rivastigmine, tacrine, and combinations thereof; and apharmaceutically acceptable carrier.

In further embodiments, the pharmaceutical compositions having featuresof the invention include pharmaceutical compositions wherein the NSCantagonist comprises a combination of compounds comprising a) at leastone compound selected from: glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, andphytoestrogens; and b) at least one compound selected from: pinkolant,flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635.

In still further embodiments, a pharmaceutical composition may comprisea pharmaceutical composition of any of the above, and further comprisinga compound effective to increase blood plasma glucose levels; forexample, a compound effective to increase blood plasma glucose levelsmay be selected from glucose and glucagon.

Embodiments of the invention disclosed herein include pharmaceuticaldosage forms comprising any of the above-described pharmaceuticalcompositions. For example, a pharmaceutical dosage form having featuresof the invention may be selected from a pill, a tablet, an oralformulation, an intravenous formulation, an intra-arterial formulation,an intramuscular formulation, a subcutaneous formulation, a peritonealformulation, an inhalational formulation, a rectal formulation, avaginal formulation, a topical formulation, a gel, an ointment, and atransdermal patch.

In embodiments, a pharmaceutical dosage form having features of theinvention includes a pharmaceutical dosage form wherein the NSCantagonist comprises a combination of compounds comprising a) at leastone compound selected from: glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, andphytoestrogens; and b) at least one compound selected from: pinkolant,flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635.

Also disclosed herein is a method of treating dementia, such as, e.g.,AD, comprising administering a NSC antagonist to a patient in need ofsuch treatment. As disclosed herein, a method of treating dementia, suchas, e.g., AD, may include administering a NSC antagonist and an othercompound used in the treatment of dementia, to a patient in need of suchtreatment. A NSC antagonist suitable for the practice of the methoddisclosed herein may be, for example, selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens,phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumicacid, rimonabant, SKF 9635, and combinations thereof. An other compoundused in the treatment of dementia, such as, e.g., AD, may be selectedfrom memantine, donepezil, galantamine, rivastigmine, tacrine, andcombinations thereof.

Also disclosed herein is a method of preventing or delaying the onset ofdementia, such as, e.g., AD, comprising administering a NSC antagonistto a patient in need of such treatment. In embodiments, a method ofpreventing or delaying the onset of dementia, such as, e.g., AD, maycomprise administering a NSC antagonist and an other compound used inthe treatment of dementia, to a patient in need of such treatment. Forexample, a NSC antagonist suitable for the practice of such methods maybe selected from glibenclamide, 4-trans-hydroxy-glibenclamide,3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide,repaglinide, nateglinide, meglitinide, midaglizole, tolazamide,gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen,estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol,zearalenone, non-steroidal estrogens, phytoestrogens, pinkolant,flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635,and combinations thereof. For example, an other compound used in thetreatment of dementia, such as , e.g., AD, may be selected frommemantine, donepezil, galantamine, rivastigmine, tacrine, andcombinations thereof.

In still further embodiments, a method of preventing or delaying theonset of dementia, such as, e.g., AD, may further compriseadministration of a compound effective to increase blood plasma glucoselevels; a compound effective to increase blood plasma glucose levels maybe, for example, selected from glucose and glucagon.

In embodiments of the methods disclosed herein, the NSC antagonistcomprises a combination of compounds comprising a) at least one compoundselected from: glibenclamide, 4-trans-hydroxy-glibenclamide,3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide,repaglinide, nateglinide, meglitinide, midaglizole, tolazamide,gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen,estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol,zearalenone, non-steroidal estrogens, and phytoestrogens; and b) atleast one compound selected from: pinkolant, flufenamic acid, mefanamicacid, niflumic acid, rimonabant, SKF 9635.

Also disclosed herein are kits, including a kit comprising apharmaceutically acceptable formulation of a NSC antagonist, and apharmaceutically acceptable formulation of an AD drug; and a kitcomprising a pharmaceutically acceptable formulation of a NSCantagonist, a pharmaceutically acceptable formulation of an AD drug, anda pharmaceutically acceptable formulation of a compound effective toincrease blood plasma glucose levels.

DETAILED DESCRIPTION

The term “Sulfonylureas” as used in the following disclosure includesSulfonylureas, Sulfonylurea mimetics, and any other drug or chemicalcompound that is effective to block or reduce the activity of channelsassociated with SUR1. In embodiments, the channels associated with SUR1include the NC_(Ca-ATP) channel (see, e.g., U.S. Patent ApplicationPublications 20030215889, “Non-selective cation channel in neural cellsand methods for treating brain swelling”; 20050181980, “Novelnon-selective cation channel in neural cells and method for treatingbrain swelling”; 20060100183, “Therapeutic agents targeting theNC_(Ca-ATP) channel and methods of use thereof”; and 20060276411. “Novelnon-selective cation channel in neuronal cells and methods for treatingbrain swelling” all of which applications are hereby incorporated byreference in their entireties) and K_(ATP) channels. In embodiments ofthe invention, the Sulfonylureas, sulfonylurea mimetics, or other drugsare NSC antagonists effective to block the channels associated withSUR1. In embodiments of the invention, the blockade of the channelsassociated with SUR1 by NSC antagonists is effective to reduce theamount of neuronal cell death associated with dementia, such as AD. Inembodiments of the invention, the blockade of the channels associatedwith SUR1 by NSC antagonists is effective to prevent neuronal fromoccurring, delay, or ameliorate cell death associated with dementia,such as AD.

The channels known as the “TRPM4 channel” and as the “TRPM5 channel” arenon-selective channels sharing many of the characteristics of theNC_(Ca-ATP) channel, and are postulated by some to be the pore-formingsubunit of the SUR1-regulated NC_(Ca-ATP) channel (see, e.g., Simard etal., Biochimica et Biophysica Acta, 1772(8):947-957 (2007)). Blockers ofthe TRPM4 channel include pinkolant((R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide));fenamates, including flufenamic acid, mefanamic acid, and niflumic acid;rimonabant (SR141716A;(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide);SKF 9635(1-(beta-[3[(4-methoxy-phenyppropoxyl]-4-methoxyphenyethyl)-1H-imidazolehydrochloride); and other compounds. As used herein, the terms “NSCantagonist” and “NSC antagonists” include blockers of the TRPM4 channel,including those listed above. In embodiments of the invention, theblockade of the TRPM4 channels by NSC antagonists is effective to reducethe amount of neuronal cell death associated with dementia, such as AD.In embodiments of the invention, the blockade of TRPM4 channels by NSCantagonists is effective to prevent from occurring, delay, or ameliorateneuronal cell death associated with dementia, such as AD.

Thus, the present invention provides compounds, pharmaceuticalcompositions, methods of treatment, and kits comprising NSC antagonistsfor treating dementia, such as AD. Such treatment may providepreventative treatment for persons not presently suffering fromdementia, such as AD, or for persons thought to be at risk fordeveloping dementia, such as AD, and may provide therapeutic treatmentfor persons suffering from dementia, such as AD, or from a dementingcondition related to AD.

In one example, a person at risk for developing AD would take a NSCantagonist such as glibenclamide in order to prevent or delay the onsetof the disease. The drug may be taken orally or transdermally, althoughit will be understood that any suitable mode of delivery (e.g.subcutaneously, intravenously (IV), intramuscularly, etc.) may be usedin the practice of the invention.

In another example, a person developing or having developed AD wouldtake a NSC antagonist such as glibenclamide in order to treat thedisease. The drug may be administered orally, topically (e.g., viatransdermal patch, or via ointment) but any suitable mode of delivery(e.g. subcutaneously, intravenously (IV), intramuscularly, etc.) may beused in the practice of the invention.

In another example, a person having developed AD may take a NSCantagonist such as glibenclamide in order to treat the disease and signsand symptoms of AD would be monitored during treatment. The drug dosagemay be adjusted upwards or downwards depending on clinical response tothe drug. The drug may be administered orally or topically (e.g., viatransdermal patch or via ointment), but any suitable mode of delivery(e.g. subcutaneously, IV, intramuscularly, etc.) may be used in thepractice of the invention.

In another example, a person developing or having developed AD and whohas concurrent diabetes may take a NSC antagonist such as glibenclamidein order to treat both the AD and diabetes. The drug may be administeredorally or topically (e.g. via transdermal patch, or ointment), but anysuitable mode of delivery (e.g. subcutaneously, intravenously (IV),intramuscularly, etc.) may be used in the practice of the invention.This dosage would need to be high enough to cause therapeutic effect forboth AD and diabetes.

The dose may be low enough to cause therapeutic effect without causinghypoglycemia, although higher doses could be used if co-treated with anagent that would prevent hypoglycemia such as glucose or glucagon. Giventhis, while doses of 2.5 mg to 20 mg per day would be permissible, lowerdoses in the range 0.01 mg/day through to 2.5 mg per day would bepreferable. Higher doses might be useful as “rescue treatments”, or atthe beginning of treatment, or intermittently to speed recovery.

Administration of NSC antagonists for ameliorating, treating, delaying,or preventing dementia, such as AD, includes administration of a singleNSC antagonist; administration of two, or of more than two, NSCantagonists; administration of one or more NSC antagonists with otherdrugs, where such other drugs may include drugs used to ameliorate,treat, delay, or prevent dementia such as AD; administration of one ormore NSC antagonists with other drugs, where such other drugs mayinclude drugs used to correct or stabilize blood glucose levels; andother forms of administration in conjunction with other drugs ortreatments. In embodiments in which administration of NSC antagonistsfor ameliorating, treating, delaying, or preventing dementia, such asAD, includes the administration of more than one NSC antagonist,suitable combinations of NSC antagonists may be provided where a) atleast one NSC antagonist compound is selected from: glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estradiol, estrone, estriol, genistein,diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, andphytoestrogens; and b) at least one NSC antagonist compound is selectedfrom: pinkolant, flufenamic acid, mefanamic acid, niflumic acid,rimonabant, SKF 9635. A NSC antagonist, such as, e.g., glibenclamide,may be administered in conjunction (either separately or together) withother compounds useful for treating AD or for ameliorating the symptomsof AD, including, e.g., drugs such as memantine (Namenda®;1-amino-3,5-dimethyl-adamantane), donepezil (Aricept®;2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one),galantamine (Nivalin ®;(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl- 6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol), rivastigmine (Exelon®;(S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamatehydrogen-(2R,3R)-tartrate), tacrine (Cognex®;1,2,3,4-tetrahydroacridin-9-amine); or other drug or drugs useful in thetreatment, prevention, palliation, or amelioration of dementia, such asAD.

The length of treatment may extend for days, months or for years, andmay comprise treatment with a NSC antagonist, or may compriseco-treatment with a SUR1 antagonist and with other drugs. In embodimentswith other drugs, such other drugs may be drugs used in treatingdementia. In preferred embodiments with other drugs, such other drugsare drugs used in treating AD. Suitable dosing regimens include singledoses per day and include multiple times per day, daily, or lessfrequent doses. Where a transdermal patch is used to administer the NSCantagonist, or combination of drugs including a NSC antagonist, thedosing regimen may include placement of the patch at a suitable place onthe skin of a subject and allowing the patch to remain in that positionfor a day, for multiple days, or for a week or multiple weeks, or for amonth, or for two or more months.

Administration

The manner in which the compounds are administered can vary. Thecompounds can be administered topically (e.g., in lotion form); orally(e.g., in liquid form within a solvent such as an aqueous or non-aqueousliquid, or within a solid carrier); intravenously (e.g., within adextrose or saline solution); as an infusion or injection (e.g., as asuspension or as an emulsion in a pharmaceutically acceptable liquid ormixture of liquids); intrathecally; intracerebro-ventricularly; ortransdermally (e.g., using a transdermal patch). Although it is possibleto administer the compounds in the form of a bulk active chemical, it ispreferred to present each compound in the form of a pharmaceuticalcomposition or formulation for efficient and effective administration.Exemplary methods for administering such compounds will be apparent tothe skilled artisan. For example, the compounds can be administered inthe form of a tablet, a hard gelatin capsule or as a time-releasecapsule. As another example, the compounds can be deliveredtransdermally using the types of patch technologies available fromNovartis and Alza Corporation (now part of Johnson and Johnson). Theadministration of the pharmaceutical compositions of the presentinvention can be intermittent, or at a gradual, continuous, constant orcontrolled rate. In addition, the time of day and the number of timesper day that the pharmaceutical formulation is administered can vary.Administration preferably is such that the active ingredients of thepharmaceutical formulation interact with receptor sites within the bodyof the subject that effect the functioning of the central nervous system(CNS). More specifically, in treating a CNS disorder administrationpreferably is such so as to optimize the effect upon those relevantreceptor subtypes which have an effect upon the functioning of the CNS,while minimizing the effects upon muscle-type receptor subtypes. Thismay include the use of slow release capsules and pills to provide bloodplasma levels of the agent that are substantially constant over time, orrelatively less varying over time than would be the case with othermodes of administration, rather than peaks and troughs associated withfast and regular-release capsules and pills. Other suitable methods foradministering the compounds of the present invention are described inU.S. Pat. No. 5,604,231 to Smith et al.

Typical dosages for systemic administration of NSC antagonists may rangefrom about 0.1 to about 1000 milligrams per kg weight of subject peradministration. A typical dosage may be one 0.4-3000 mg tablet takenonce a day, or one time-release capsule or tablet taken once a day andcontaining a proportionally higher content of active ingredient. Thetime-release effect may be obtained by capsule materials that dissolveat different pH values, by capsules that release slowly by osmoticpressure, or by any other known means of controlled release (see, e.g.,osmotic drug delivery advice as shown, e.g., in U.S. Pat. No. 5,312,390;slow-release compositions as discussed, e.g., in U.S. Pat. No.5,411,737).

Sulfonylurea Receptor 1 Antagonists are NSC antagonists

Sulfonylureas and compounds that act at, and antagonize the activationor activity of, sulfonylurea receptors such as SUR1, are useful as NSCantagonists. Glibenclamide is an exemplary NSC antagonist, and is namedherein as an example of one of the NSC antagonists that are suitable forthe practice of the embodiments of the invention disclosed herein.Glibenclamide is also known as glybenclamide, glyburide,glybenzcyclamide, and by other names. The chemical name (IUPAC name) ofglibenclamide is 5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxy-benzamide. Equivalent chemical names forglibenclamide include, e.g.,5-chloro-N-[2-[4-[[[cyclohexylamino)carbonyl]amino]sulfonyl]phenyl]ethyl]-2-methoxy-benzamide(as reported in the Merck Index (12^(th) Edition, Merck ResearchLaboratories, 1996, page 762), and1[p-2[5-chloro-O-anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexyl-3-urea.

It will be understood that any NSC antagonist is suitable for thepractice of the embodiments of the invention disclosed herein, and thatnaming glibenclamide is not meant to be limiting. Other suitable NSCantagonists include, in addition to, glibenclamide: glibenclamide'sactive metabolites, such as (for example) 4-trans-hydroxy-glibenclamideand 3-cis-hydroxy-glibenclamide; tolbutamide (orinase®;3-butyl-1-(4-methylphenyl)sulfonyl-urea); chlorpropamide(N-(4-chlorophenyl)sulfonylmethanamide; also given as1-[[(p-chlorophenyl)sulfonyl]-3-propylurea); glipizide(1-cyclohexyl-3[[p-[2(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl] urea); ortolazamide(benzenesulfonamide-N-[[(hexahydro-1H-azepin-1yl)amino]carbonyl] -4-methyl), repaglinide, nateglinide(N-trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine), meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, estrogen, estrogen related-compounds (estradiol, estrone,estriol, genistein, non-steroidal estrogen (e.g., diethystilbestrol),phytoestrogen (e.g., coumestrol), zearalenone, etc.), and combinationsthereof Examples of suitable NSC antagonists further include, but arenot limited to, compounds known to inhibit or block K_(KR) channels(which include, without limitation, tolbutamide, glibenclamide, andother compounds named above, as well as MgADP, and other compounds).

NSC antagonists include compounds that block or reduce the physiologicalactivity of the TRPM4 channel. NSC antagonists which are blockers of theTRPM4 channel include pinkolant((R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide));fenamates, including flufenamic acid, mefanamic acid, and niflumic acid;rimonabant (SR141716A;(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide);SKF 9635(1-(beta-[3[(4-methoxy-phenyl)propoxyl]-4-methoxyphenyethyl)-1H-imidazolehydrochloride); and other compounds.

Dose Determinations

Any suitable medicament, pharmaceutical formulation, and dosage form maybe used in the practice of the invention. A suitable medicament,pharmaceutical formulation, and dosage form is effective to deliver orprovide a therapeutically effective amount of the drug or drugcombination to the patient. For example, suitable pharmaceutical dosageforms include a pill, a tablet, an oral formulation, a gel, an ointment,a transdermal patch, an intravenous solution, a formulation forintramuscular administration, a formulation for peritonealadministration, and a formulation for subcutaneous administration.Pharmaceutical dosage forms may be designed to provide stable plasmalevels for extended periods of time. Thus, suitable pharmaceuticaldosage forms include forms for injection; oral forms; topical forms;tablets, pills, capsules, gels, and so forth; sustained release forms,enteric-coated forms, implantable forms including depot and pump forms,and other pharmaceutical forms.

By a “therapeutically effective amount” or simply “effective amount” ofan active compound, such as glibenclamide or tolbutamide, is meant asufficient amount of the compound to treat, prevent or alleviate AD or acondition related to AD. It will be understood, however, that the totaldaily usage of the active compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disease;activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coinciding with the specificcompound employed; and like factors well known in the medical arts.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell assays or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds which exhibit large therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage and,thereby, reduce side effects.

Data obtained from cell culture assays and animal studies can be used informulating a range of dosage for use in humans. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED₅₀ with little or no toxicity. The dosage may varywithin this range depending upon the dosage form employed and the routeof administration utilized. For any compound used in the method of theinvention, the therapeutically effective dose can be estimated initiallyfrom cell based assays. A dose may be formulated in animal models toachieve a circulating plasma concentration range that includes the IC₅₀(i.e., the concentration of the test compound which achieves ahalf-maximal inhibition of symptoms) as determined in cell culture. Suchinformation can be used to more accurately determine useful doses inhumans. Levels in plasma may be measured, for example, by highperformance liquid chromatography.

The total daily dose of the active compounds of the present inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 25 mg or more usually from 0.1 to 15mg. It will be understood that dosages will vary between the differentNSC antagonists. However, in general, in embodiments, dosages may bebetween about 0.4 mg to about 3000 mg. In preferred embodiments, forexample, glibenclamide dosages may be between about 0.4 mg to about 10mg. Single dose compositions may contain such amounts or submultiplesthereof to make up the daily dose. In general, treatment regimensaccording to the present invention comprise administration to a human orother mammal in need of such treatment from about 0.01 mg to about 5 mgper day, or up to about 1000 mg of the active substance(s) of thisinvention per day in multiple doses or in a single dose of from 0.01 mg,0.1 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 100 mg, 500 mg or 1000 mg.

An effective amount of a NSC antagonist or related-compounds thereof asa treatment varies depending upon the subject that is treated and theparticular mode of administration. In one embodiment of the inventionthe dose range of the NSC antagonist or related-compounds thereof willbe about 0.01 μg/kg body weight to about 20,000 μg/kg body weight. Allconcentrations and treatment levels are expressed as “body weight” orsimply “kg” in this application are also considered to cover theanalogous “total body weight” concentrations. However, those of skillwill recognize the utility of a variety of dosage range, for example,0.01 μg/kg body weight to 20,000 μg/kg body weight, 0.02 μg/kg bodyweight to 15,000 μg/kg body weight, 0.03 μg/kg body weight to 10,000μg/kg body weight, 0.04 μg/kg body weight to 5,000 μg/kg body weight,0.05 μg/kg body weight to 2,500 μg/kg body weight, 0.06 μg/kg bodyweight to 1,000 μg/kg body weight, 0.07 μg/kg body weight to 500 μg/kgbody weight, 0.08 μg/kg body weight to 400 μg/kg body weight, 0.09 μg/kgbody weight to 200 μg/kg body weight or 0.1 μg/kg body weight to 100μg/kg body weight. Further, those of skill will recognize that a varietyof different dosage levels will be of use, for example, 0.0001 μg/kg,0.0002 μg/kg, 0.0003 μg/kg, 0.0004 μg/kg, 0.005 μg/kg, 0.0007 μg/kg,0.001 μg/kg, 0.1 μg/kg, 1.0 μg/kg, 1.5 μg/kg, 2.0 μg/kg, 5.0 μg/kg, 10.0μg/kg, 15.0 μg/kg, 30.0 μg/kg, 50 μg/kg, 75 μg/kg, 80 μg/kg, 90 μg/kg,100 μg/kg, 120 μg/kg, 140 μg/kg, 150 μg/kg, 160 μg/kg, 180 μg/kg, 200μg/kg, 225 μg/kg, 250 μg/kg, 275 μg/kg, 300 μg/kg, 325 μg/kg, 350 μg/kg,375 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600 μg/kg, 700μg/kg, 750 μg/kg, 800 μg/kg, 900 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 12mg/kg, 15 mg/kg, 20 mg/kg, and/or 30 mg/kg. Of course, all of thesedosages are exemplary, and any dosage in-between these points is alsoexpected to be of use in the invention. Any of the above dosage rangesor dosage levels may be employed for a NSC antagonist orrelated-compounds thereof.

For example, in certain embodiments, the amount of the NSC antagonistadministered to the subject is in the range of about 0.0001 μg/kg/day toabout 20 mg/kg/day, about 0.01 μg/kg/day to about 100 μg/kg/day, orabout 100 μg/kg/day to about 20 mg/kg/day. Still further, the NSCantagonist may be administered to the subject in the from of a treatmentin which the treatment may comprise the amount of the NSC antagonist orthe dose of the NSC antagonist that is administered per day (1, 2, 3, 4,etc.), week (1, 2, 3, 4, 5, etc.), month (1, 2, 3, 4, 5, etc.), etc.Treatments may be administered such that the amount of NSC antagonistadministered to the subject is in the range of about 0.0001μg/kg/treatment to about 20 mg/kg/treatment, about 0.01 μg/kg/treatmentto about 100 μg/kg/treatment, or about 100 μg/kg/treatment to about 20mg/kg/treatment.

In embodiments, a NSC antagonist dosage may be between about 0.01 mg toabout 15 mg. In preferred embodiments, a dosage may be between about 0.4mg to about 10 mg per day. For example, a suitable daily dose ofglibenclamide may be less than about 10 mg per day; in particularembodiments, a suitable daily dose of glibenclamide may be about 0.4mg/day to about 10 mg/day, or about 4-9 mg per day, or about 5-8 mg perday, or other amount as determined by the weight, age, sex, liver andkidney status, or other characteristic of the patient. Dosage forms,such as pills including a NSC antagonist as an active ingredient, alongwith other ingredients such as pharmaceutically acceptable excipients,may include, for example, about 10 mg, or about 5 mg, or about 2.5 mg,or about 1 mg, or about 0.5 mg, or about 0.1 mg of glibenclamide.

It is believed that suitable glibenclamide doses useful for treating ADwill typically result in blood plasma concentrations of about 2-6 ng/mlor higher. Thus, in embodiments, treatments will result in suitableblood plasma concentrations of about 5 ng/ml, or of about 4 ng/ml, or ofabout 3 ng/ml, or of about 2 ng/ml, or of about 1 ng/ml, or higher bloodplasma concentrations.

In alternative embodiments, for example, a suitable dose of oral orintravenous (IV) glibenclamide for the treatment of AD may be about 0.01mg to about 10 mg per day; a suitable dose of oral or IV tolbutamide forthe treatment of AD may be about to 0.001 mg to about 3,000 mg per day;a suitable dose of oral gliclazide for the treatment of AD may be about0.1 mg to about 100 mg per day;

In certain situations, it may be important to maintain a fairly low doseof the active agent in the blood stream of the patient. Such a fairlylow dose may include a dose that is less than its use in otherindications. For example, the typical anti-diabetic dose of oralglibenclamide is about 2.5 mg to about 15 mg per day; the typicalanti-diabetic dose of oral or IV tolbutamide is about to 500 mg to about3000 mg per day; the typical anti-diabetic dose for oral gliclazide isabout 30 mg to about 120 mg per day; however, in embodiments, smallerdoses may be used in treatment of AD. Where smaller doses are used, suchsmaller doses may be, for example, less than about 2.5 mg/day ofglibenclamide, less than about 500 mg per day of tolbutamide, less thanabout 30 mg per day of oral gliclazide, or other doses. Such smallerdoses may be used, for example, where multiple doses are administeredduring the course of a single day, effective to reduce the variabilityin the plasma levels of the drug over time. In particular, it isbelieved that preferred dosages of glibenclamide for use according tothe present invention provide between about 0.4 mg to about 10 mgglibenclamide per day; preferred dosages of tolbutamide for useaccording to the present invention provide between about 50 mg to about1000 mg tolbutamide per day; and preferred dosages of gliclazide for useaccording to the present invention provide between about 5 mg to about20 mg gliclazamide per day.

In certain situations, it may be important to maintain a fairly highdose of the active agent in the blood stream of the patient,particularly early in the treatment. Such a fairly high dose may includea dose that is several times greater than its use in other indications.For example, the typical anti-diabetic dose of oral glibenclamide isabout 2.5 mg to about 15 mg per day; the typical anti-diabetic dose oforal tolbutamide is about to 0.5 gm to about 3.0 gm per day; the typicalanti-diabetic dose for oral gliclazide is about 30 mg to about 120 mgper day; however, larger doses may be required in some cases.

For example, in one embodiment of the present invention directed to amethod of preventing or treating AD in a subject by administering to thesubject a formulation containing an effective amount of a NSC antagonistand a pharmaceutically acceptable carrier; such formulations maycontain, for example, from about 0.01 to about 3000 milligrams oftolbutamide or from about 0.05 to about 50 milligrams of glibenclamide.

In regards to oral glibenclamide for AD in non diabetics, doses may bein the range 0.1 mg/day to 10 mg/day or even as high as 15-20 mg/day,and would be divided into low dose pills given as few as 1 doses a day,and as many as 4-6 doses. Dose regimens are designed so as to maintainthe plasma concentrations of glibenclamide, or of any other NSCantagonist, steady over time, and so as to, as much as possible, avoidor minimize large peaks and valleys or plasma concentration over time.Administration more than twice a day is often associated with lowcompliance, thus it is considered that in practice maximal numbers ordoses per day may be about 4-6 doses per day.

A preferred method of administration includes transdermal administrationof NSC antagonist, such as by use of a transdermal patch. For example,transdermal glibenclamide patches as presently used for treatment ofdiabetes may be used in the methods disclosed herein, as adapted toprovide proper dosage levels of NSC antagonist, such as glibenclamide,for treatment, palliation, amelioration, or prevention of AD.

A NSC antagonist may be administered intravenously. For example, whereglibenclamide is administered to a patient for the treatment of AD,smaller amounts of glibenclamide may be required to obtain a bloodplasma level of about 6 ng/ml, so that, for example, as little as about0.5 mg/day glibenclamide may be administered intravenously.

A suitable amount of NSC antagonist may also be an amount that maintainsa reasonable level of blood glucose in the patient, for example, theamount of the antagonist maintains a blood glucose level of at least 60mg/dl. More preferably, the blood glucose level is maintained in therange of about 60 mg/dl to about 150 mg/dl. Thus, the amount of NSCantagonist may be provided so as to prevents the subject from becominghypoglycemic. If glucose levels are not normal, then one of skill in theart would administer either insulin or glucose, depending upon if thepatient is hypoglycemic or hyperglycemic.

Glucose may be administered with a NSC antagonist in embodiments of thepresent methods of preventing or treating AD in a subject. Thus, inembodiments of the methods disclosed herein, the methods includeco-administration of a NSC antagonist with glucose, or with a relatedcarbohydrate, or both, effective to maintain appropriate levels of serumglucose. Appropriate serum levels of blood glucose are within the rangeof about 60 mg/dl to about 150 mg/dl. Thus, glucose, or a relatedcarbohydrate, or both, may be administered, alone or in combination, tomaintain the serum glucose within this range or within.

A NSC antagonist such as glibenclamide may be administered inconjunction (either separately or together) with drugs used for treatingAD patients such as, e.g., memantine (Namenda®;1-amino-3,5-dimethyl-adamantane), donepezil (Aricept®;2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one),galantamine (Nivalin ®;(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol),rivastigmine (Exelon®;(S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamatehydrogen-(2R,3R)-tartrate), or other drugs useful in the treatment,prevention, palliation, or amelioration of AD. Such drugs used fortreating AD patients are termed “AD drugs.” Administration of NSCantagonists in conjunction with AD drugs includes, without limitation:simultaneous or concomitant administration of a NSC antagonist with anAD drug; administration of a NSC antagonist followed by administrationof an AD drug; and administration of an AD drug followed byadministration of a NSC antagonist. Simultaneous or concomitantadministration includes administration of both drugs, or of both typesof drugs, within a few minutes or within a few tens of minutes of eachother.

Accordingly, compositions and pharmaceutical formulations of the presentinvention include combined dosage forms including as active ingredientsa NSC antagonist and another drug. The other drug is preferably a drugthat is used in the treatment of AD, or a drug that is useful in thetreatment of AD. In embodiments, the other drug may be memantine, ordonepezil, or galantamine, or rivastigmine, or tacrine, or anycombination thereof. Combined pills having features of the inventioninclude pills providing suitable amounts of NSC antagonist, as discussedabove. Thus, for example, where the NSC antagonist is glibenclamide, acombined dosage form may include in a single pill, tablet, capsule, orother dosage form, for example, glibenclamide with memantine;glibenclamide with donepezil; glibenclamide with galantamine;glibenclamide with rivastigmine; or glibenclamide with tacrine.Similarly, where the NSC antagonist is tolbutamide, a combined dosageform may include in a single pill, tablet, capsule, or other dosageform, for example, tolbutamide with memantine; tolbutamide withdonepezil; glibenclamide with galantamine; tolbutamide withrivastigmine; or tolbutamide with tacrine. It will be understood that acombined dosage form may include in a single pill, tablet, capsule, orother dosage form having features of the invention any combination of aNSC antagonist and a drug used in, or useful for, treating AD, and mayinclude more than one NSC antagonist; more than one drug used in, oruseful for, treating AD; and may include more than one of both a NSCantagonist and more than one drug used in, or useful for, treating AD.

For example, a single pill, tablet, capsule, or other dosage form havingfeatures of the invention may include about 0.4-5 mg glibenclamide withabout 5-10 mg memantine. Other examples, listed to provide examples butnot to limit the single pill, tablet, capsule, or other dosage formsdisclosed herein, include about 1-5 mg glibenclamide with about 5-10 mgdonepezil; about 1-5 mg glibenclamide with about 1-5 mg rivastigmine;about 1-5 mg glibenclamide with about 4-12 mg galantamine; about 1-5 mgglibenclamide with about 10-40 mg tacrine; and other combinations.

A transdermal patch having features of the invention may combine activeingredients a NSC antagonist and another drug. The other drug ispreferably a drug that is used in the treatment of AD, or a drug that isuseful in the treatment of AD. In embodiments, the other drug may bememantine, or donepezil, or galantamine, or rivastigmine, or tacrine, orany combination thereof. Combined transdermal patches having features ofthe invention include pills providing suitable amounts of NSCantagonist, as discussed above. Thus, for example, where the NSCantagonist is glibenclamide, a combined transdermal patch may include,for example, glibenclamide with memantine; glibenclamide with donepezil;glibenclamide with galantamine; glibenclamide with rivastigmine; orglibenclamide with tacrine. Similarly, where the NSC antagonist istolbutamide, a combined transdermal patch may include, for example,tolbutamide with memantine; tolbutamide with donepezil; glibenclamidewith galantamine; tolbutamide with rivastigmine; or tolbutamide withtacrine. It will be understood that a transdermal patch having featuresof the invention may include any combination of a NSC antagonist and adrug used in, or useful for, treating AD, and may include more than oneNSC antagonist; more than one drug used in, or useful for, treating AD;and may include more than one of both a NSC antagonist and more than onedrug used in, or useful for, treating AD.

Methods

Applicants disclose herein that the onset of dementia may be preventedor delayed, and that dementia may be treated, or its symptoms relieved,by administration of an effective amount of a NSC antagonist to apatient at risk of developing dementia, or suffering from the onset ofdementia, or suffering from dementia. The dementia may be AD. The NSCantagonist may be, for example, glibenclamide, glibenclamide's activemetabolites (e.g., 4-trans-hydroxy-glibenclamide and3-cis-hydroxy-glibenclamide), tolbutamide, chlorpropamide, tolazamide,repaglinide, nateglinide, meglitinide, midaglizole, tolazamide,gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen,estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol,zearalenone, non-steroidal estrogens, phytoestrogens, or a combinationthereof. In embodiments, the NSC antagonist is selected fromglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide,nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364,LY389382, glyclazide, glimepiride, and combinations thereof.

Applicants further disclose herein that the onset of dementia may beprevented or delayed, and that dementia may be treated, or its symptomsrelieved, by administration of an effective amount of a NSC antagonistin combination with an other drug that is used to treat dementia, to apatient at risk of developing dementia, or suffering from the onset ofdementia, or suffering from dementia. The dementia may be AD. The NSCantagonist may be glibenclamide, tolbutamide, chlorpropamide,tolazamide, repaglinide, nateglinide, meglitinide, midaglizole,tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride,estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol,coumestrol, zearalenone, non-steroidal estrogens, phytoestrogens, or acombination thereof. In embodiments, the NSC antagonist is selected fromglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide,nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364,LY389382, glyclazide, glimepiride, and combinations thereof. The otherdrug that is used to treat dementia may be, for example, selected frommemantine, donepezil, galantamine, rivastigmine, tacrine, andcombinations thereof.

In further embodiments of the methods disclosed herein, a substance isadministered to the patient effective to maintain blood plasma glucoselevels within an acceptable physiological concentration range. In someembodiments, the substance is glucose. In some embodiments, thesubstance is glucagon. In some embodiments, both glucose and glucagonare administered.

In further embodiments of the methods disclosed herein, blood plasmaglucose levels are monitored. Blood glucose level monitoring may beperformed before administration of a NSC antagonist, or beforeadministration of a NSC antagonist with an other dementia drug, orbefore administration of a substance effective to maintain blood plasmaglucose levels within an acceptable physiological range, or beforeadministration of a NSC antagonist with an other dementia drug and witha substance effective to maintain blood plasma glucose levels within anacceptable physiological range.

In further embodiments, blood glucose level monitoring may be performedduring administration of a NSC antagonist, or during administration of aNSC antagonist with an other dementia drug, or during administration ofa substance effective to maintain blood plasma glucose levels within anacceptable physiological range, or during administration of a NSCantagonist with an other dementia drug and with a substance effective tomaintain blood plasma glucose levels within an acceptable physiologicalrange.

Blood glucose level monitoring may be performed after administration ofa NSC antagonist, or after administration of a NSC antagonist with another dementia drug, or after administration of a substance effective tomaintain blood plasma glucose levels within an acceptable physiologicalrange, or after administration of a NSC antagonist with an otherdementia drug and with a substance effective to maintain blood plasmaglucose levels within an acceptable physiological range.

In further embodiments, blood glucose level monitoring may be performedat any time with respect to the administration of a NSC antagonist, orthe administration of a NSC antagonist with an other dementia drug, orthe administration of a substance effective to maintain blood plasmaglucose levels within an acceptable physiological range, or theadministration of a NSC antagonist with an other dementia drug and witha substance effective to maintain blood plasma glucose levels within anacceptable physiological range.

Blood plasma concentrations of glibenclamide of as low as 2-6 ng/ml areeffective to statistically significant reductions in blood plasmaglucose levels in some patients. Thus in an embodiment, blood plasmalevels of glibenclamide are maintained at about 2-6 ng/ml or more. Infurther embodiments, glucose is provided in order to maintain bloodglucose levels within the desirable range (typically above about 60mg/dl, or between about 60 mg/dl to about 150 mg/dl). Glucose may beadministered at the same time as the glibenclamide; may be administeredat different times (e.g., before or after glibenclamide administration);and glucose may be administered by another route of administration (orseparate pill) in order to keep blood plasma glucose levels within thedesirable range. In embodiments of the methods of the invention, glucoselevels may be monitored. For example, a glucose monitoring system may beused monitor glucose levels and to aid in determining the proper amountsof glucose to be administered in order to adjust glucose administrationspecifically for that particular patient. Such a glucose monitoringsystem may be one-time glucose monitoring system; may be an intermittentglucose monitoring system; and may be a continuous glucose monitoringsystem.

Formulations and Administration

The NSC antagonist compounds for use in the compositions, formulations,methods, and kits of the present invention may be administered alone orin combination or in concurrent therapy with other agents which affectthe central or peripheral nervous system, particularly selected areas ofthe brain. Compositions and formulations suitable for the practice ofthe invention include pharmaceutical dosage forms that are suitable foradministration by one or more of any suitable route of administration,and include a pill, a tablet, an oral formulation, an intravenousformulation, an intra-arterial formulation, an intramuscularformulation, a subcutaneous formulation, a peritoneal formulation, aninhalational formulation, a rectal formulation, a vaginal formulation, atopical formulation, a gel, an ointment, and a transdermal patch.

In compositions, formulations, methods and kits of the invention, NSCantagonist compounds can be incorporated into a pharmaceuticallyacceptable formulation for administration. Those of skill in the art canreadily determine suitable dosage levels when the invention compoundsare so used. In embodiments of the invention, compositions andformulations comprising at least one NSC antagonist compound, and apharmaceutically acceptable carrier are contemplated.

As employed herein, the phrase “suitable dosage levels” refers to levelsof compound sufficient to provide circulating concentrations high enoughto prevent or treat dementia, such as AD, in a patient. In embodimentsof the invention, such dosages are effective to block the NC_(Ca-ATP)channel in vivo.

Pharmaceutical dosage forms include a NSC antagonists or apharmaceutically acceptable salt, solvate, or solvate of a salt thereof,and one or more pharmaceutical excipients. As is known in the art,pharmaceutical excipients are secondary ingredients which function toenable or enhance the delivery of a drug or medicine in a variety ofdosage forms (e.g.: oral forms such as tablets, capsules, and liquids;topical forms such as dermal, opthalmic, and otic forms; suppositories;injectables; respiratory forms and the like). Pharmaceutical excipientsinclude inert or inactive ingredients, synergists or chemicals thatsubstantively contribute to the medicinal effects of the activeingredient. For example, pharmaceutical excipients may function toimprove flow characteristics, product uniformity, stability, taste, orappearance, to ease handling and administration of dose, for convenienceof use, or to control bioavailability. While pharmaceutical excipientsare commonly described as being inert or inactive, it is appreciated inthe art that there is a relationship between the properties of thepharmaceutical excipients and the dosage forms containing them.

Pharmaceutical excipients suitable for use as carriers or diluents arewell known in the art, and may be used in a variety of formulations.See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. R.Gennaro, Editor, Mack Publishing Company (1990); Remington: The Scienceand Practice of Pharmacy, 20th Edition, A. R. Gennaro, Editor,Lippincott Williams & Wilkins (2000); Handbook of PharmaceuticalExcipients, 3rd Edition, A. H. Kibbe, Editor, American PharmaceuticalAssociation, and Pharmaceutical Press (2000); and Handbook ofPharmaceutical Additives, compiled by Michael and Irene Ash, Gower(1995), each of which is incorporated herein by reference for allpurposes.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs containing inert diluents commonly used in the art, such aswater, isotonic solutions, or saline. Such compositions may alsocomprise adjuvants, such as wetting agents; emulsifying and suspendingagents; sweetening, flavoring and perfuming agents.

Oral solid dosage forms such as tablets will typically comprise one ormore pharmaceutical excipients, which may for example help impartsatisfactory processing and compression characteristics, or provideadditional desirable physical characteristics to the tablet. Suchpharmaceutical excipients may be selected from diluents, binders,glidants, lubricants, disintegrants, colors, flavors, sweetening agents,polymers, waxes or other solubility-retarding materials.

Compositions for intravenous administration will generally compriseintravenous fluids, i.e., sterile solutions of simple chemicals such assugars, amino acids or electrolytes, which can be easily carried by thecirculatory system and assimilated. Such fluids are prepared with waterfor injection USP.

Dosage forms for parenteral administration will generally comprisefluids, particularly intravenous fluids, i.e., sterile solutions ofsimple chemicals such as sugars, amino acids or electrolytes, which canbe easily carried by the circulatory system and assimilated. Such fluidsare typically prepared with water for injection USP. Fluids usedcommonly for intravenous (IV) use are disclosed in Remington, TheScience and Practice of Pharmacy [full citation previously provided],and include: alcohol, e.g., 5% alcohol (e.g., in dextrose and water(“D/W”) or D/W in normal saline solution (“NSS”), including in 5%dextrose and water (“D5/W”), or D5/W in NSS); synthetic amino acid suchas Aminosyn, FreAmine, Travasol, e.g., 3.5 or 7; 8.5; 3.5, 5.5 or 8.5%respectively; ammonium chloride e.g., 2.14%; dextran 40, in NSS e.g.,10% or in D5/W e.g., 10%; dextran 70, in NSS e.g., 6% or in D5/W e.g.,6%; dextrose (glucose, D5/W) e.g., 2.5-50%; dextrose and sodium chloridee.g., 5-20% dextrose and 0.22-0.9% NaCl; lactated Ringer's (Hartmann's)e.g., NaCl 0.6%, KCl 0.03%, CaCl.sub.2 0.02%; lactate 0.3%; mannitole.g., 5%, optionally in combination with dextrose e.g., 10% or NaCle.g., 15 or 20%; multiple electrolyte solutions with varyingcombinations of electrolytes, dextrose, fructose, invert sugar Ringer'se.g., NaCl 0.86%, KCl 0.03%, CaCl.sub.2 0.033%; sodium bicarbonate e.g.,5%; sodium chloride e.g., 0.45, 0.9, 3, or 5%; sodium lactate e.g., 1/6M; and sterile water for injection The pH of such IV fluids may vary,and will typically be from 3.5 to 8 as known in the art.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulation can be sterilized, for example, by filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions, which can be dissolvedor dispersed in sterile water or other sterile injectable medium justprior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of a drug from subcutaneous or intramuscular injection.The most common way to accomplish this is to inject a suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug becomes dependent on the rate of dissolutionof the drug, which is, in turn, dependent on the physical state of thedrug, for example, the crystal size and the crystalline form. Anotherapproach to delaying absorption of a drug is to administer the drug as asolution or suspension in oil. Injectable depot forms can also be madeby forming microcapsule matrices of drugs and biodegradable polymers,such as polylactide-polyglycoside. Depending on the ratio of drug topolymer and the composition of the polymer, the rate of drug release canbe controlled. Examples of other biodegradable polymers includepolyorthoesters and polyanhydrides. The depot injectables can also bemade by entrapping the drug in liposomes or microemulsions, which arecompatible with body tissues.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient, such as cocoabutter and polyethylene glycol which are solid at ordinary temperaturebut liquid at the rectal temperature and will, therefore, melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, gelcaps and granules. In such solid dosageforms the active compound may be admixed with at least one inert diluentsuch as sucrose, lactose or starch. Such dosage forms may also comprise,as is normal practice, additional substances other than inert diluents,e.g., tableting lubricants and other tableting aids such as magnesiumstearate and microcrystalline cellulose. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings andother release-controlling coatings.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,capsules, pills, and granules can be prepared with coatings and shellssuch as enteric coatings and other coatings well known in thepharmaceutical formulating art. They may optionally contain opacifyingagents and can also be of a composition that they release the activeingredient(s) only, or preferably, in a certain part of the intestinaltract, optionally in a delayed manner. Examples of embeddingcompositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches.

Pharmaceutical compositions for topical administration may include theactive compound formulated for a medicated application such as anointment, paste, cream or powder. Ointments include all oleaginous,adsorption, emulsion and water-solubly based compositions for topicalapplication, while creams and lotions are those compositions thatinclude an emulsion base only. Topically administered medications maycontain a penetration enhancer to facilitate absorption of the activeingredients through the skin. Suitable penetration enhancers includeglycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones andluarocapram. Possible bases for compositions for topical applicationinclude polyethylene glycol, lanolin, cold cream and petrolatum as wellas any other suitable absorption, emulsion or water-soluble ointmentbase. Topical preparations may also include emulsifiers, gelling agents,and antimicrobial preservatives as necessary to preserve the activeingredient and provide for a homogenous mixture. The ointments, pastes,creams and gels may contain, in addition to an active compound of thisinvention, excipients such as animal and vegetable fats, oils, waxes,paraffins, starch, tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc and zinc oxide, ormixtures thereof.

Transdermal administration of the present invention may also comprisethe use of a “patch”. For example, the patch may supply one or moreactive substances at a predetermined rate and in a continuous mannerover a fixed period of time. Transdermal patches have the addedadvantage of providing controlled delivery of active compound to thebody. Such dosage forms can be made by dissolving or dispersing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel. In addition, a patchmay include penetration enhancers. Suitable penetration enhancersinclude glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones andluarocapram.

Exemplary pharmaceutically acceptable carriers include carriers suitablefor oral, intravenous, subcutaneous, intramuscular, intracutaneous, andthe like administration. Administration in the form of creams, lotions,tablets, dispersible powders, granules, syrups, elixirs, sterile aqueousor non-aqueous solutions, suspensions or emulsions, and the like, iscontemplated.

For the preparation of oral liquids, suitable carriers includeemulsions, solutions, suspensions, syrups, and the like, optionallycontaining additives such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring and perfuming agents, and the like.

For the preparation of fluids for parenteral administration, suitablecarriers include sterile aqueous or non-aqueous solutions, suspensions,or emulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized, for example,by filtration through a bacteria-retaining filter, by incorporatingsterilizing agents into the compositions, by irradiating thecompositions, or by heating the compositions. They can also bemanufactured in the form of sterile water, or some other sterileinjectable medium immediately before use. The active compound is admixedunder sterile conditions with a pharmaceutically acceptable carrier andany needed preservatives or buffers as may be required.

In certain embodiments, the pharmaceutical compositions may be deliveredby eye drops, intranasal sprays, inhalation, and/or other aerosoldelivery vehicles. Methods for delivering compositions directly to thelungs via nasal aerosol sprays has been described e.g., in U.S. Pat.Nos. 5,756,353 and 5,804,212 (each specifically incorporated herein byreference in its entirety). Likewise, the delivery of drugs usingintranasal microparticle resins (Takenaga et al., 1998) andlysophosphatidyl-glycerol compounds (U.S. Pat. No. 5,725,871,specifically incorporated herein by reference in its entirety) are alsowell-known in the pharmaceutical arts. Likewise, transmucosal drugdelivery in the form of a polytetrafluoroetheylene support matrix isdescribed in U.S. Pat. No. 5,780,045 (specifically incorporated hereinby reference in its entirety).

The term aerosol refers to a colloidal system of finely divided solid ofliquid particles dispersed in a liquefied or pressurized gas propellant.The typical aerosol of the present invention for inhalation will consistof a suspension of active ingredients in liquid propellant or a mixtureof liquid propellant and a suitable solvent. Suitable propellantsinclude hydrocarbons and hydrocarbon ethers. Suitable containers willvary according to the pressure requirements of the propellant.Administration of the aerosol will vary according to subject's age,weight and the severity and response of the symptoms.

Therapeutic kits of the present invention are kits comprising anantagonist or a related-compound thereof. Thus, the kit may comprise anNSC antagonist or related-compound thereof to block and/or inhibit theNC_(Ca-ATP) channel or to block or inhibit a TRPM4 channel. Such kitswill generally contain, in suitable container means, a pharmaceuticallyacceptable formulation of NSC antagonist or related-compound thereof;may contain, in suitable container means, a pharmaceutically acceptableformulation of an AD drug or related-compound thereof; and may include acompound effective to raise or to maintain, at suitable levels, bloodplasma glucose concentrations. The kit may have a single containermeans, and/or it may have distinct container means for each compound.

A pharmaceutically acceptable formulation is a composition, including atleast one active ingredient, and including one or more otheringredients, such as, for example, diluents, solutions, buffers,carriers, excipients, binders, extenders, osmoticants, and othercompounds and ingredients as are suitable for dissolving, storing,and/or delivering an active pharmaceutical agent.

Kits comprising pharmaceutical compositions and/or formulations suitablefor preventing AD, or for treating AD, may include instructions foradministration of the pharmaceutical compositions and/or formulations,and may include containers suitable for holding the pharmaceuticalcompositions and/or formulations. Such containers of such kits may besuitable for organizing pills, vials, or other unit dosage forms fordaily, weekly or other dosage regimens.

Kits may comprise a pharmaceutically acceptable formulation of a NSCantagonist, and a pharmaceutically acceptable formulation of an AD drug.IN embodiments, a kit may comprise a pharmaceutically acceptableformulation of a NSC antagonist, a pharmaceutically acceptableformulation of an AD drug, and a pharmaceutically acceptable formulationof a compound effective to increase blood plasma glucose levels. Acompound effective to increase blood plasma glucose levels may be, forexample, glucagon, or glucose, or both, or other compound.

When the components of the kit are provided in one and/or more liquidsolutions, the liquid solution is an aqueous solution, with a sterileaqueous solution being particularly preferred. The NSC antagonist orrelated-compounds thereof may also be formulated into a syringeablecomposition. In which case, the container means may itself be a syringe,pipette, and/or other such like apparatus, from which the formulationmay be applied to an infected area of the body, injected into an animal,and/or even applied to and/or mixed with the other components of thekit.

In addition to the NSC antagonist or related-compounds thereof, the kitsmay also include a second active ingredient. Examples of the secondactive ingredient include substances to prevent hypoglycemia (e.g.,glucose, glucagon, glucose solutions such as 5% dextrose in water (D5W),and other substances), and steroids (e.g., methylprednisolone), etc.These second active ingredients may be combined in the same vial as theNSC antagonist or related-compounds thereof or they may be contained ina separate vial.

All patents and publications discussed herein are hereby incorporated byreference in their entireties.

EXAMPLES

The following exemplary descriptions illustrate ways to implement themethods and treatments disclosed herein.

A 56-year old man with a family history of AD in his grandfather, fatherand elder sibling presents to a neurologist concerned about his risk ofAD. Upon examination he is found to be cognitively normal, with noclinical signs of neurological disease. The patient is begun on a lowdose of daily glibenclamide of 0.5 mg per day for transdermaladministration, to be taken on a chronic basis as a prophylactictreatment.

A 56-year old man with a family history of AD in his grandfather, fatherand elder sibling presents to a neurologist concerned about his risk ofAD. Upon examination he is found to be cognitively normal, with noclinical signs of neurological disease. The patient is begun on a lowdose of daily glibenclamide of 0.5 mg per day for oral administration,to be taken on a chronic basis as a prophylactic treatment.

The daughter of an 83-year old female notices her mother exhibitingepisodes of forgetfulness, and a situation in which the mother is unableto locate her car in a shopping center parking lot. The elderly patientis brought to a geriatrician, where mini-mental state examinationreveals short-term memory loss and mild cognitive impairment. Adiagnosis of AD is made as other causes are ruled out. The patientbegins a course of daily glibenclamide of 1.0 mg per day administeredvia monthly depot intramuscular injection. Depot injection is chosen inorder to optimize patient compliance. Neurological testing detects astabilization of symptoms due to the treatment.

A 68-year old type 2 diabetic male presents to his family physician withcomplaints of forgetfulness and increasing confusion. He is beingtreated with metformin and diet controls for his Type 2 diabetes. Thepatient is diagnosed with AD upon referral to a geriatrician and uponclinical, laboratory and imaging investigations. The patient begins adaily dose of glibenclamide at 10 mg per day, and his daily metformin isceased. The patient demonstrates stable blood glucose measurements andHbA1C levels, and the patient notes that his episodes of forgetfulnessare waning with this treatment regimen.

1-20. (canceled)
 21. A method of treating dementia, comprisingadministering an NSC antagonist to a patient in need of such treatment,wherein said NSC antagonist comprises an antagonist of activity of theNC.sub.Ca-ATP channel, the TRPM4 channel, or the TRPM5 channel.
 22. Themethod of claim 21, wherein said dementia is Alzheimer's Disease (AD).23. The method of claim 21, wherein said NSC antagonist is selected fromglibenclamide, 4-trans-hydroxy-glibenclamide,3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide,repaglinide, nateglinide, meglitinide, midaglizole, tolazamide,gliquidone, LY397364, LY389382, glyclazide, glimepiride, pinkolant,flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635,and combinations thereof.
 24. The method of claim 21, wherein the NSCantagonist is selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, gliquidone, LY397364, LY389382, glyclazide, glimepiride,25. The method of claim 21, wherein the NSC antagonist is selected fromthe group consisting of pinkolant, flufenamic acid, mefanamic acid,niflumic acid, rimonabant, SKF 9635, and combinations thereof.
 26. Themethod of claim 21, wherein the NSC antagonist is glibenclamide.
 27. Themethod of claim 21, wherein treating dementia comprises preventing ordelaying the onset of AD.
 28. The method of claim 21, wherein said NSCantagonist is selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, pinkolant, flufenamic acid, mefanamic acid, niflumic acid,rimonabant, SKF 9635, and combinations thereof.
 29. The method of claim22, wherein said other compound used in the treatment of dementia isselected from memantine, donepezil, galantamine, rivastigmine, tacrine,and combinations thereof.
 30. The method of claim 22, further comprisingadministration of a compound effective to increase blood plasma glucoselevels.
 31. The method of claim 22, further comprising administration ofanother compound, wherein said other compound is a compound used in thetreatment of dementia.
 32. The method of claim 31, wherein said dementiais Alzheimer's Disease (AD).
 33. The method of claim 31, wherein saidNSC antagonist is selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, pinkolant, flufenamic acid, mefanamic acid, niflumic acid,rimonabant, SKF 9635, and combinations thereof.
 34. The method of claim31, wherein said other compound used in the treatment of dementia isselected from memantine, donepezil, galantamine, rivastigmine, tacrine,and combinations thereof.
 35. The method of claim 31, wherein the NSCantagonist is selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, gliquidone, LY397364, LY389382, glyclazide, glimepiride,36. The method of claim 31, wherein the NSC antagonist is selected fromthe group consisting of pinkolant, flufenamic acid, mefanamic acid,niflumic acid, rimonabant, SKF 9635, and combinations thereof
 37. Themethod of claim 31, wherein the NSC antagonist is glibenclamide.
 38. Themethod of claim 31, wherein treating dementia comprises preventing ordelaying the onset of AD.
 39. A pharmaceutical composition comprising aNSC antagonist; a compound used in the treatment of dementia; and apharmaceutically acceptable carrier.
 40. The pharmaceutical compositionof claim 39, wherein said NSC antagonist is selected from glibenclamide,4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide,chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide,midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide,glimepiride, pinkolant, flufenamic acid, mefanamic acid, niflumic acid,rimonabant, SKF 9635, and combinations thereof.
 41. The pharmaceuticalcomposition of claim 39, wherein said compound used in the treatment ofdementia is selected from memantine, donepezil, galantamine,rivastigmine, tacrine, and combinations thereof.
 42. The pharmaceuticalcomposition of claim 39 comprising glibenclamide; a compound selectedfrom memantine, donepezil, galantamine, rivastigmine, tacrine, andcombinations thereof; and a pharmaceutically acceptable carrier.
 43. Thepharmaceutical composition of claim 39 comprising tolbutamide; acompound selected from memantine, donepezil, galantamine, rivastigmine,tacrine, and combinations thereof; and a pharmaceutically acceptablecarrier.
 44. The pharmaceutical composition of claim 39 comprisingchlorpropamide; a compound selected from memantine, donepezil,galantamine, rivastigmine, tacrine, and combinations thereof and apharmaceutically acceptable carrier.
 45. The pharmaceutical compositionof claim 39, further comprising a compound effective to increase bloodplasma glucose levels.
 46. The pharmaceutical composition of claim 45,wherein said compound effective to increase blood plasma glucose levelsis selected from glucose and glucagon.